Trial Outcomes & Findings for Bioequivalence Study of Temozolomide in Patients With Primary Tumors of the Central Nervous System (NCT NCT02343081)

Last Updated: 2015-04-02

Results Overview

Rate of absorption of Temozolomide (Cmax) will be measured after the oral administration of the test product (Dralitem®, Monte Verde S.A.) or the reference product (Temodal®, Schering-Plough).

Recruitment status

COMPLETED

Study phase

PHASE4

Target enrollment

24 participants

Primary outcome timeframe

0, 0.25, 0.5, 0.75, 1.0, 1.25, 1.5, 1.75, 2.0, 2.5, 3.0, 4.0, 6.0, 8.0, 10.0 hours on Days 3 and 4

Results posted on

2015-04-02

Participant Flow

This study enrolled patients with primary tumours of the Central Nervous System (CNS) excluding patients with primary CNS lymphoma, from FLENI Clinical-Surgical Diagnosis and Treatment Institute, Buenos Aires, Argentina. The last patient completed in October 2013.

Of the initial sample size of 24 patients, 19 were effectively screened during a period from October 2012 and October 2013; 3 patients did not meet inclusion criteria and 16 were randomized to the two intervention arms.

Participant milestones

Participant milestones
Measure	Temodal, Then Dralitem During days 1 and 2, all patients received a single oral dose of 200 mg/m2 of Temozolomide from Monte Verde S.A. (Dralitem®). On day 3 patients received 200 mg/m2 of Temozolomide from Schering-Plough (Temodal®) as a single oral dose. After a washout period of 10 hours, they then received 200 mg/m2 of Temozolomide from Monte Verde S.A. (Dralitem®). On day 5 all patients received Temozolomide 200 mg/m2 from Monte Verde S.A. (Dralitem®).All patients were under fasting conditions two hours before and after each drug administration.	Dralitem, Then Temodal During days 1 and 2, all patients received a single oral dose of 200 mg/m2 of Temozolomide from Monte Verde S.A. (Dralitem®). On day 3 patients received 200 mg/m2 of Temozolomide from Monte Verde S.A. (Dralitem®) as a single oral dose. After a washout period of 10 hours, they then received 200 mg/m2 of Temozolomide from Schering-Plough (Temodal®). On day 5 all patients received Temozolomide 200 mg/m2 from Monte Verde S.A.(Dralitem®). All patients were under fasting conditions two hours before and after each drug administration.
First Intervention (Day 3) STARTED	8	8
First Intervention (Day 3) Received Intervention	8	8
First Intervention (Day 3) COMPLETED	8	8
First Intervention (Day 3) NOT COMPLETED	0	0
Washout (10 Hours) STARTED	8	8
Washout (10 Hours) COMPLETED	8	8
Washout (10 Hours) NOT COMPLETED	0	0
Second Intervention (Day 4) STARTED	8	8
Second Intervention (Day 4) Received Intervention	8	8
Second Intervention (Day 4) COMPLETED	8	8
Second Intervention (Day 4) NOT COMPLETED	0	0

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

Bioequivalence Study of Temozolomide in Patients With Primary Tumors of the Central Nervous System

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Temodal, Then Dralitem n=8 Participants During days 1 and 2, all patients received a single oral dose of 200 mg/m2 of Temozolomide from Monte Verde S.A. (Dralitem®). On day 3 patients received 200 mg/m2 of Temozolomide from Schering-Plough (Temodal®) as a single oral dose. After a washout period of 10 hours, they then received 200 mg/m2 of Temozolomide from Monte Verde S.A. (Dralitem®). On day 5 all patients received Temozolomide 200 mg/m2 from Monte Verde S.A. (Dralitem®).All patients were under fasting conditions two hours before and after each drug administration.	Dralitem, Then Temodal n=8 Participants During days 1 and 2, all patients received a single oral dose of 200 mg/m2 of Temozolomide from Monte Verde S.A. (Dralitem®). On day 3 patients received 200 mg/m2 of Temozolomide from Monte Verde S.A. (Dralitem®) as a single oral dose. After a washout period of 10 hours, they then received 200 mg/m2 of Temozolomide from Schering-Plough (Temodal®). On day 5 all patients received Temozolomide 200 mg/m2 from Monte Verde S.A.(Dralitem®). All patients were under fasting conditions two hours before and after each drug administration.	Total n=16 Participants Total of all reporting groups
Age, Continuous	53.75 Years STANDARD_DEVIATION 9.35 • n=99 Participants	39.75 Years STANDARD_DEVIATION 14.5 • n=107 Participants	48.44 Years STANDARD_DEVIATION 14.5 • n=206 Participants
Sex: Female, Male Female	4 Participants n=99 Participants	3 Participants n=107 Participants	7 Participants n=206 Participants
Sex: Female, Male Male	4 Participants n=99 Participants	5 Participants n=107 Participants	9 Participants n=206 Participants
Region of Enrollment Argentina	8 participants n=99 Participants	8 participants n=107 Participants	16 participants n=206 Participants
Height	169 cm STANDARD_DEVIATION 9.53 • n=99 Participants	173.37 cm STANDARD_DEVIATION 8.65 • n=107 Participants	170.00 cm STANDARD_DEVIATION 8.00 • n=206 Participants
Weight, Continuous	78.87 kg STANDARD_DEVIATION 14.20 • n=99 Participants	81.12 kg STANDARD_DEVIATION 10.78 • n=107 Participants	79.40 kg STANDARD_DEVIATION 12.00 • n=206 Participants
Body Surface, Continuous	1.89 m^2 STANDARD_DEVIATION 0.22 • n=99 Participants	1.95 m^2 STANDARD_DEVIATION 0.16 • n=107 Participants	1.92 m^2 STANDARD_DEVIATION 0.19 • n=206 Participants
Body Mass Index	26.03 kg/m^2 STANDARD_DEVIATION 2.01 • n=99 Participants	28.46 kg/m^2 STANDARD_DEVIATION 2.72 • n=107 Participants	27.26 kg/m^2 STANDARD_DEVIATION 2.82 • n=206 Participants

PRIMARY outcome

Timeframe: 0, 0.25, 0.5, 0.75, 1.0, 1.25, 1.5, 1.75, 2.0, 2.5, 3.0, 4.0, 6.0, 8.0, 10.0 hours on Days 3 and 4

Population: All those subjects who completed the study and were compliant with all the protocol procedures were considered evaluable for statistical pharmacokinetic analysis. Those who received at least one dose of the products under study but did not comply with the study procedures were included in the safety analysis only.

Rate of absorption of Temozolomide (Cmax) will be measured after the oral administration of the test product (Dralitem®, Monte Verde S.A.) or the reference product (Temodal®, Schering-Plough).

Outcome measures

Outcome measures
Measure	Temodal n=16 Participants Temozolomide (Schering-Plough) 200 mg/m2, single oral dose. Temozolomide	Dralitem n=16 Participants Temozolomide (Monte Verde S.A.) 200 mg/m2, single oral dose Temozolomide
Cmax	11.108 mcg/mL Standard Deviation 2.486	10.575 mcg/mL Standard Deviation 2.805

PRIMARY outcome

Timeframe: 0, 0.25, 0.5, 0.75, 1.0, 1.25, 1.75, 2.0, 2.5, 3.0, 4.0, 6.0, 8.0, 10.0 hours on Days 3 and 4

Extent of absorption of Temozolomide from time (0) to the last quantifiable concentration (t) will be measured after the oral administration of the test product (Dralitem®, Monte Verde S.A.) or the reference product (Temodal®, Schering-Plough)

Outcome measures

Outcome measures
Measure	Temodal n=16 Participants Temozolomide (Schering-Plough) 200 mg/m2, single oral dose. Temozolomide	Dralitem n=16 Participants Temozolomide (Monte Verde S.A.) 200 mg/m2, single oral dose Temozolomide
AUC0-t	30.796 mcg*h/mL Standard Deviation 3.893	31.104 mcg*h/mL Standard Deviation 4.019

PRIMARY outcome

Timeframe: 0, 0.25, 0.5, 0.75, 1.0, 1.25, 1.5, 1.75, 2.0, 2.5, 3.0, 4.0, 6.0, 8.0, 10.0 hours on Days 3 and 4

Extent of absorption of Temozolomide from time (0) to infinity (∞) will be measured after oral administration of the test product (Dralitem®, Monte Verde S.A.) or the reference product (Temodal®, Schering-Plough).

Outcome measures

Outcome measures
Measure	Temodal n=16 Participants Temozolomide (Schering-Plough) 200 mg/m2, single oral dose. Temozolomide	Dralitem n=16 Participants Temozolomide (Monte Verde S.A.) 200 mg/m2, single oral dose Temozolomide
AUC0-∞	31.817 mcg*h/mL Standard Deviation 4.159	32.290 mcg*h/mL Standard Deviation 4.174

SECONDARY outcome

Timeframe: Up to two weeks post last dose

AEs and SAEs will be collected from the start of study treatment and until two weeks post last dose. If AEs or SAEs extend in time and are not resolved before the end of the 2-week follow up period, this period shall last until the event/s are resolved.

Outcome measures

Outcome data not reported

OTHER_PRE_SPECIFIED outcome

Timeframe: 0, 0.25, 0.5, 0.75, 1.0, 1.25, 1.5, 1.75, 2.0, 2.5, 3.0, 4.0, 6.0, 8.0, 10.0 hours on Days 3 and 4

Rate at which Temozolomide is removed from the body.

Outcome measures

Outcome measures
Measure	Temodal n=16 Participants Temozolomide (Schering-Plough) 200 mg/m2, single oral dose. Temozolomide	Dralitem n=16 Participants Temozolomide (Monte Verde S.A.) 200 mg/m2, single oral dose Temozolomide
Kel	0.3743 1/h Standard Deviation 0.0451	0.3691 1/h Standard Deviation 0.0258

OTHER_PRE_SPECIFIED outcome

Timeframe: 0, 0.25, 0.5, 0.75, 1.0, 1.25, 1.5, 1.75, 2.0, 2.5, 3.0, 4.0, 6.0, 8.0, 10.0 hours on Days 3 and 4

Time required for Temozolomide plasma concentration to decrease by 50%

Outcome measures

Outcome measures
Measure	Temodal n=16 Participants Temozolomide (Schering-Plough) 200 mg/m2, single oral dose. Temozolomide	Dralitem n=16 Participants Temozolomide (Monte Verde S.A.) 200 mg/m2, single oral dose Temozolomide
T1/2	1.87 hours Standard Deviation 0.20	1.89 hours Standard Deviation 0.13

Adverse Events

Temodal

Serious events: 0 serious events

Other events: 5 other events

Deaths: 0 deaths

Dralitem

Serious events: 0 serious events

Other events: 4 other events

Deaths: 0 deaths

Serious adverse events

Adverse event data not reported

Other adverse events

Additional Information

Dr. Alejandro Muggeri (Principal Investigator)

FLENI- mrc (FLENI Multi-specialty Research Center)

Phone: 54-11-5777 3200

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Measure	Temodal n=16 participants at risk Temozolomide (Schering-Plough) 200 mg/m2, single oral dose.	Dralitem n=16 participants at risk Temozolomide (Monte Verde S.A.) 200 mg/m2, single oral dose.
Skin and subcutaneous tissue disorders Itchy Rash	6.2% 1/16 • Eighteen days for each arm (Safety Surveillance Period). Safety population included all subjects who received at least one dose of intervention.	0.00% 0/16 • Eighteen days for each arm (Safety Surveillance Period). Safety population included all subjects who received at least one dose of intervention.
Gastrointestinal disorders Vomiting	6.2% 1/16 • Eighteen days for each arm (Safety Surveillance Period). Safety population included all subjects who received at least one dose of intervention.	0.00% 0/16 • Eighteen days for each arm (Safety Surveillance Period). Safety population included all subjects who received at least one dose of intervention.
Gastrointestinal disorders Gastritis	6.2% 1/16 • Eighteen days for each arm (Safety Surveillance Period). Safety population included all subjects who received at least one dose of intervention.	0.00% 0/16 • Eighteen days for each arm (Safety Surveillance Period). Safety population included all subjects who received at least one dose of intervention.
Metabolism and nutrition disorders Hyporexia	6.2% 1/16 • Eighteen days for each arm (Safety Surveillance Period). Safety population included all subjects who received at least one dose of intervention.	0.00% 0/16 • Eighteen days for each arm (Safety Surveillance Period). Safety population included all subjects who received at least one dose of intervention.
Vascular disorders Leg Edema	6.2% 1/16 • Eighteen days for each arm (Safety Surveillance Period). Safety population included all subjects who received at least one dose of intervention.	0.00% 0/16 • Eighteen days for each arm (Safety Surveillance Period). Safety population included all subjects who received at least one dose of intervention.
Nervous system disorders Weakness	6.2% 1/16 • Eighteen days for each arm (Safety Surveillance Period). Safety population included all subjects who received at least one dose of intervention.	0.00% 0/16 • Eighteen days for each arm (Safety Surveillance Period). Safety population included all subjects who received at least one dose of intervention.
Nervous system disorders Dizziness	6.2% 1/16 • Eighteen days for each arm (Safety Surveillance Period). Safety population included all subjects who received at least one dose of intervention.	0.00% 0/16 • Eighteen days for each arm (Safety Surveillance Period). Safety population included all subjects who received at least one dose of intervention.
Nervous system disorders Loss of taste	6.2% 1/16 • Eighteen days for each arm (Safety Surveillance Period). Safety population included all subjects who received at least one dose of intervention.	0.00% 0/16 • Eighteen days for each arm (Safety Surveillance Period). Safety population included all subjects who received at least one dose of intervention.
Nervous system disorders Adynamia	6.2% 1/16 • Eighteen days for each arm (Safety Surveillance Period). Safety population included all subjects who received at least one dose of intervention.	0.00% 0/16 • Eighteen days for each arm (Safety Surveillance Period). Safety population included all subjects who received at least one dose of intervention.
Gastrointestinal disorders Abdominal Pain	6.2% 1/16 • Eighteen days for each arm (Safety Surveillance Period). Safety population included all subjects who received at least one dose of intervention.	0.00% 0/16 • Eighteen days for each arm (Safety Surveillance Period). Safety population included all subjects who received at least one dose of intervention.
Gastrointestinal disorders Heartburn	0.00% 0/16 • Eighteen days for each arm (Safety Surveillance Period). Safety population included all subjects who received at least one dose of intervention.	6.2% 1/16 • Eighteen days for each arm (Safety Surveillance Period). Safety population included all subjects who received at least one dose of intervention.
Gastrointestinal disorders Diarrhea	0.00% 0/16 • Eighteen days for each arm (Safety Surveillance Period). Safety population included all subjects who received at least one dose of intervention.	6.2% 1/16 • Eighteen days for each arm (Safety Surveillance Period). Safety population included all subjects who received at least one dose of intervention.
Nervous system disorders Expressive aphasia	0.00% 0/16 • Eighteen days for each arm (Safety Surveillance Period). Safety population included all subjects who received at least one dose of intervention.	6.2% 1/16 • Eighteen days for each arm (Safety Surveillance Period). Safety population included all subjects who received at least one dose of intervention.
General disorders Fever syndrome	0.00% 0/16 • Eighteen days for each arm (Safety Surveillance Period). Safety population included all subjects who received at least one dose of intervention.	6.2% 1/16 • Eighteen days for each arm (Safety Surveillance Period). Safety population included all subjects who received at least one dose of intervention.
Gastrointestinal disorders Proctorrhagia	0.00% 0/16 • Eighteen days for each arm (Safety Surveillance Period). Safety population included all subjects who received at least one dose of intervention.	6.2% 1/16 • Eighteen days for each arm (Safety Surveillance Period). Safety population included all subjects who received at least one dose of intervention.
Gastrointestinal disorders Constipation	0.00% 0/16 • Eighteen days for each arm (Safety Surveillance Period). Safety population included all subjects who received at least one dose of intervention.	6.2% 1/16 • Eighteen days for each arm (Safety Surveillance Period). Safety population included all subjects who received at least one dose of intervention.